Addressing the mechanism of priming of dopamine receptors and its effect on drug-induced dyskinesia

GERSHANIK OS; I. TARAVINI; P. BALLESTERO; FERRARIO JE; G. GOMEZ

París

Congreso; Biennal Meeting of the International Society for Neurochemistry and the European Society for Neurochemistry; 2017

International Society for Neurochemistry and the European Society for Neurochemistry

Parkinson?s disease (PD) is characterized by dopamine (DA) depletion in the striatum and its gold standard of treatment is still the use of 3,4-dihydroxyphenyl-l-alanine (L-DOPA), which after prolonged use induces severe motor complications, known as L-DOPA-induced dyskinesia (LID). Not all dopaminergic agonists share the same capacity to induce dyskinesia, and D2 agonists are frequently used in clinical practice because its low propensity to induce dyskinesia. Priming is defined as the behavioral and molecular sensitization occurring after the first exposure to L-DOPA or a full DA agonist. Priming is not necessarily associated with dyskinesia but once it has occurred, lower doses of L-DOPA or dopamine agonists are enough to induce dyskinesia. Priming has been studied by pharmacological approaches but the underlying molecular mechanism is not well understood. The aim of this work is to understand the mechanisms of priming and evaluate the effect of D1/D2 receptor stimulation on subsequent DA receptor agonist responses. C57BL/6 mice injected with 6-OHDA received a dyskinetogenic dose of L-DOPA or saline for 7 days to induce priming, and the effect of the D2 agonist Quinpirole on the development of dyskinesia was tested. We compared Quinpirole-induced dyskinesia after increasing doses vs prolonged treatment with the maximum dose of Quinpirole, and observed higher dyskinesia scores in primed vs non-primed animals. Immunohistochemistry of striatal FosB and cFos, showed increased levels of both dyskinesia markers in primed mice compared to saline pre-treated. Furthermore, we analyzed selective cFos expression in D1R expressing cells, using bacterial artificial chromosome transgenic mice expressing tdTomato in striatal projection neurons that express D1 receptor. We reproduced L-DOPA priming and Quinpirole administration protocol, and observed significant cFos immunoreactivity in D1R expressing neurons in primed mice but was almost insignificant in non-primed mice. These results confirm once again the importance of behavioral sensitization and increased dyskinesia marker expression after D1/D2 receptor stimulation. Furthermore, they demonstrate that D2 receptor stimulation has a great impact onto D1R expressing cells only after priming and shows the important role of D2 receptor in dyskinesia development, even though current concepts emphasize the role of D1 receptor as the major player in dyskinesia induction.